Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells
Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells
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DOI：
10.1172/jci89452
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发表时间：
2017-04-03
影响因子：
15.9
通讯作者：
Scadden, David T.
中科院分区：
文献类型：
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作者：
Kalaitzidis, Demetrios;Lee, Dongjun;Scadden, David T.
mTOR途径是细胞持久性和生长的关键决定因素，其中mTOR复合物1（mTORC 1）介导生长因子刺激和营养可用性之间的平衡。氨基酸或葡萄糖通过诱导mTORC 1的RagA GTdR募集至溶酶体外表面来促进mTORC 1活化，使得mTOR能够被Ras同源物Rheb活化。因此，RagA在营养丰富或缺乏的时候改变mTORC1驱动的生长。在这里，我们通过RagA和mTORC 1在造血祖细胞（动态驱动成熟细胞产生）和造血干细胞（HSC）（提供静止细胞储备）中评估了差异营养感应依赖性。在营养丰富的条件下，RagA缺陷的HSC功能未受损，并通过营养不敏感机制上调mTORC1。RagA也在营养应激条件下对HSC的功能起重要作用。类似地，RagA的过度活化不影响HSC功能。相反，RagA缺乏显着改变祖细胞群功能和成熟细胞输出。因此，RagA是区分反应性祖细胞与储备干细胞库的功能属性的分子机制。HSC通过RagA对营养感测的冷漠有助于其对营养应激的分子弹性，这一特征与进化中的生物体生存能力和现代HSC移植方法有关。
The mTOR pathway is a critical determinant of cell persistence and growth wherein mTOR complex 1 (mTORC1) mediates a balance between growth factor stimuli and nutrient availability. Amino acids or glucose facilitates mTORC1 activation by inducing RagA GTPase recruitment of mTORC1 to the lysosomal outer surface, enabling activation of mTOR by the Ras homolog Rheb. Thereby, RagA alters mTORC1-driven growth in times of nutrient abundance or scarcity. Here, we have evaluated differential nutrient-sensing dependence through RagA and mTORC1 in hematopoietic progenitors, which dynamically drive mature cell production, and hematopoietic stem cells (HSC), which provide a quiescent cellular reserve. In nutrient-abundant conditions, RagA-deficient HSC were functionally unimpaired and upregulated mTORC1 via nutrient-insensitive mechanisms. RagA was also dispensable for HSC function under nutritional stress conditions. Similarly, hyperactivation of RagA did not affect HSC function. In contrast, RagA deficiency markedly altered progenitor population function and mature cell output. Therefore, RagA is a molecular mechanism that distinguishes the functional attributes of reactive progenitors from a reserve stem cell pool. The indifference of HSC to nutrient sensing through RagA contributes to their molecular resilience to nutritional stress, a characteristic that is relevant to organismal viability in evolution and in modern HSC transplantation approaches.